AstraZeneca’s big MYSTIC trial ends a complete failure as Imfinzi/tremelimumab combo flops on overall survival

Last year, AstraZeneca preached patience after initial data showed its checkpoint inhibitor Imfinzi combined with their in-house CTLA-4 drug failed to meet the primary endpoint of progression-free survival in a pivotal lung cancer trial. On Friday, that faith proved in vain as the immunotherapy also failed to improve overall survival in the keenly watched MYSTIC trial.

The trial tested Imfinzi both as a monotherapy and in combination with another checkpoint inhibitor, tremelimumab, against chemotherapy in treatment-naive patients with stage IV non-small cell lung cancer (NSCLC), a crucial arena in the battle for checkpoint drug dominance.

The pharma giant $AZN conceded Friday morning that the combination — once considered a cornerstone of AstraZeneca’s checkpoint development strategy — actually performed worse than Imfinzi alone for the overall survival endpoint, with a hazard ratio of 0.76 for the solo drug compared to an anemic 0.85 for the two together.

Sean Bohen

While AstraZeneca’s pipeline has often come up short, there have been a string of major successes in oncology for the company. This trial was considered critical in putting the brakes on the blitzing gains Merck $MRK and Bristol-Myers Squibb have made after establishing their lead in the lucrative frontline cancer field. The study was also touted by CEO Pascal Soriot as an indicator of the British drugmaker’s value as an independent entity, when it spurned Pfizer’s $PFE $118 billion takeover bid in 2014

In a statement on Friday, AstraZeneca also suggested that although statistical significance for overall survival had not been met, the data merited further analysis in exploratory subgroups. That’s not likely going to inspire much enthusiasm.

Brad Loncar

In MYSTIC, “CTLA-4 truly offered no benefit or signal at all”, said Brad Loncar, manager of the Loncar Cancer Immunotherapy ETF. “I would think hard about these results if I was one of the companies out there developing me-too or me-better CTLA-4s (of which there are many). Given its toxicity profile and now the emerging combo efficacy we are seeing in some of these cancers outside of melanoma, its window is looking quite narrow.”

AstraZeneca’s shares were also under pressure again on the failure. Its stock is down more than 3% in pre-market trading. Shares fell sharply last year on the PFS miss, evaporating some $14 billion off the company’s value.

Since that initial setback on MYSTIC, though, AstraZeneca scored a big win with its PACIFIC trial for Imfinzi, winning a significant market niche for itself in stage III NSCLC. But the failure here will sting, nevertheless.

Chief medical officer Sean Bohen spotlighted the success on the monotherapy side, but conceded the key failure:

We are encouraged to see that Imfinzi monotherapy activity is in-line with that of the anti-PD-1 class in previously-untreated patients with Stage IV non-small cell lung cancer; however, we are disappointed that these results missed statistical significance. We remain confident in Imfinzi as the cornerstone of our IO programme and continue to evaluate its potential in ongoing non-small cell lung cancer trials, including Imfinzi and Imfinzi plus tremelimumab in combination with chemotherapy.

Image: Pascal Soriot. AP IMAGES

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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